Osteoporosis, defined by low bone density leading to increased risk of fractures, afflicts many millions in the U.S. Measurement of bone density, together with evaluation of risk factors (e.g., sex, age, and race; low intake of calcium and vitamin D; and chronic exposure to alcohol, cigarette smoke, or glucocorticoids), provides the beast means to identify susceptible individuals. Bone density is largely under genetic control, with heritability-the genetic portion of variance calculated at 60-80%. This proposal seeks to identify gene regions responsible for low bone density in a mouse model of osteoporosis, the SAMP6 strain, and to test them for a similar effect in humans. When SAMP6 mice are crossed to either of two control strains, bone density varies widely among the "grandchildren" of such crosses. By scanning the genome for locations segregating with bone density, and thus associated with it, genes influencing that trait can be positioned. At least 5 high significant genetic regions have been identified that govern bone density of mature mice, and other, distinct loci were found that affect post-maturity change in bone density. To more precisely map some of these genetic regions, offspring of crosses will be mated to one parental strain, and progeny inheriting the implicated region from the other strain will be detected using strain-specific markers. That process is repeated for 8-10 generations, with selection of late-arising recombinants, to create lines of mice retaining only part of a marked region from the "donor" strain, isolated in the "recipient" genetic backgrounds. By defining overlaps among donor segments of many such lines, and measuring bone density for many such lines, the area affecting bone density can be narrowed to a precise span, and then subdivided by further recombinants. Genes in these smaller intervals will be sequenced to reveal differences among the three strains, and bone related traits will be characterized for each line to ascertain divergence from the nearly identical recipient strain. The corresponding gene regions will be tested for linkage to bone density in extended human families, and individuals at genes within a narrowed interval, which distinguish between humans having high vs. low bone density. Such studies may give insights into the genetic regulation of bone density and molecular mechanisms underlying osteoporosis.